Our project combines the emerging fields of glycoscience and mechanobiology with a single overarching goal - to decipher how cellular glycans physically regulate signal transduction. Our central hypothesis is that chemical and mechanical signals integrate in space and time within the sugar-rich cell surface coating called the glycocalyx. This project will develop new technologies for imaging and characterizing the biophysical properties of the cellular glycocalyx with the goal of unraveling its fundamental mechanobiology. We will investigate how sugars and large glycoproteins physically impact receptor trafficking, spatial organization, and signaling activity. The principles learned will significantly advance our understanding of how cells detect, interpret, and respond to chemical and mechanical signals. Furthermore, our project will address how metabolism and sugar biosynthesis regulate the mechano-phenotype of cells and will define new paradigms for the biophysical consequences of metabolic reprograming in cancer, diabetes, and aging. Leveraging computational and experimental biology, physics, and molecular imaging, our work has the potential to transform our understanding of glycans in the physical functioning of living systems.